Keith J Barrington
CHU Sainte Justine
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Problems of definition
A continuum of lung injury
Arbitrarily divided into BPD/non-BPD
depending on duration of O2 therapy
Criteria for O2 therapy differ (hence the
“physiologic definition”)
Long term effects rarely examined
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long term pulmonary outcomes
neurodevelopmental impairment
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To provide evidence based guidelines for
prevention of BPD
Review of the literature
Hierarchy of evidence
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Steroids
TRH
Antibiotics
No proven effect on BPD, reduce mortality, therefore
probably improve survival without BPD
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Surfactant therapy; preparation, dose, timing
Ventilatory management
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High frequency
Early CPAP
Permissive hypercapnia
Synchronized ventilation
early extubation
Oxygen therapy
Inhaled nitric oxide
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Fluid management
Nutrition; calories, protein and fat.
PDA management
Vitamin A
Postnatal steroids
Ureaplasma and therapies for it
Diuretics
Antioxidants; SOD, vitamin E
Caffeine
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Oxygen
Ventilation
Intubation /surfactant
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No evidence of different starting FiO2 and BPD
risk
No evidence of different target SpO2 and BPD risk
No evidence for PEEP during DR ventilation or for
measuring and limiting tidal volume
 All likely to be important
 Can’t see any reason not to use PEEP
 Currently could use 30% to start, target progressively
increasing saturations, PEEP of 4 to 6, avoid too much chest
rise
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Preventing lung injury is essential, injury
which may be initiated in the first few
minutes of life.
There are a number of studies comparing
rescue to prophylactic treatment.
One study compared early rescue with
very early rescue (Osiris study) The
difference in median administration
times was 64 minutes. 11% less BPD with
earlier rescue
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The Osiris collaborative group. Early versus delayed neonatal
administration of synthetic surfactant - The judgement of OSIRIS.
Lancet. 1992;340:1363-69
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Risk difference for BPD or death is 0.045, giving an
NNT of 22.
To prevent one death the NNT is 17
Babies treated prophylactically are more likely to
need only one dose
Overall mean number of doses received are 1.2 per
prophylaxis baby and 1.5 per rescue baby.
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Controls were either all intubated or just given O2 as required,
no routine use of CPAP in the controls
So if you have a ventilated preterm in the DR who
needs oxygen, immediate surfactant should be
given
Is prophylactic surfactant better than immediate
CPAP with early rescue?
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COIN
SUPPORT
VON (Dunn et al)
CURPAP
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610 infants of 25+0 to 28+6 weeks.
If breathing at 5 min and needing respiratory
support randomised to immediate nasal CPAP
at 8 cm H2O, or intubation
Intubation rate first 5 days for the CPAP group
46% (55% for 25+26 w and 40% for 27+28 w).
Intubated group treated according to local
practice (77% got surfactant)
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Apnea unresponsive to stimulation and
methlyxanthine treatment (>6 episodes
requiring stimulation in 6 hours or requiring >1
episode of positive-pressure ventilation),
Arterial pH < 7.25 with a
PaCO2 > 60 mm Hg,
Metabolic acidosis not responsive to treatment,
Or > 60% FiO2
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1316 infants 24 weeks to 27 weeks
intubation and surfactant treatment (within 1
hour after birth) or
CPAP treatment initiated in the delivery room,
with subsequent use of a protocol-driven
limited ventilation strategy.
Intubated infants weaned to rate of 20 within
24 hous if possible and if PCO2 < 50, FiO2
<35%
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FIO2 > 0.50 for SpO2 >= at or above 88%
PaCO2 > 65 mm Hg; or hemodynamic
instability, defined as a blood pressure that was
low for gestational age, poor perfusion, or both,
requiring volume or pressor support for a
period of 4 hours or more.
Infants who were intubated within the first 48
hours after birth were to receive surfactant.
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208 infants 25 to 28 wk GA
CPAP in the DR if stabilisable
Then randomized to INSURE at 30 minutes of
age, extubated in less than an hour if possible
Comparison group remained on CPAP
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1 of the following:
FIO2 > 0.4 for SpO2 85% to 92% for > 30
minutes unless rapid clinical deterioration
Apnea defined as 4 per hour or 2 per hour if
bag and mask required,
Respiratory acidosis defined as PCO2 65 mm
Hg (8.5 kPa), and pH 7.2 on arterial or capillary
blood gas
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640 infants 26 to 29 weeks GA, 3 groups:
Surf Prophylaxis
Prophylactic INSURE
CPAP
Intubation criteria
>12 apneas needing stimulation or > 1 that required
bagging in 6-h;
 PCO2 >65 mm Hg;
 FIO2 of >0.4 to maintain sat 86% - 94%.
 Intubation discretionary if FIO2 0.4 to 0.6 and mandatory
if FIO2 > 0.6. After intubation, infants on O2 received
surfactant.
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If the baby can be stabilized without
intubation:
CPAP installed in the delivery room
Uninterrupted CPAP during transfer to NICU
Administration of surfactant as soon as it
becomes clear that the infant will need it
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How to decide this?
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Mariani G, Cifuentes J, Carlo WA: Randomized
trial of permissive hypercapnia in preterm
infants. Pediatrics 1999, 104:1082-8.
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Pilot study 49 infants 601-1250 g, less than 24h
of age
Randomized to hypercapnia (45-55 torr) or
normocapnia (35-45 torr)
Shorter duration of ventilation, trend to less
BPD, shorter O2 therapy, no change in ivh, pvl
with permissive hypercapnia.
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Carlo et al 1999/2002 NICHD network study
terminated early because of steroid
complications
Therefore insufficient power
Compared goal PCO2 >52 to goal <48 mmHg
Duration of ventilation reduced
O utco m e
D eath o r neuro deve lo p m e nta l
im pa irm e nt
D eath by fo llo w -u p
N euro deve l. im pa irm e nt
C erebra l p a ls y
B ilatera l blind ne ss
D ea fness
M D I < 70
P D I < 70
R e ho sp ita lizat io ns
M inim a l
ve nt ilat io n
64
R o utine
ve nt ilat io n
68
R e lative risk (95%
C I)
0.95 (0.78 – 1.16)
P
va lue
.62
24
51
11
1
6
47
32
55
27
55
20
0
5
43
33
62
0.94 (0.69 – 1.28)
0.92 (0.68 – 1.26)
0.55 (0.25 – 1.21)
.70
.62
.14
.50
.93
.62
.95
.42
45% reduction in cerebral palsy!!!, p=NS
1.06
1.10
0.98
0.89
(0.27 – 4.07)
(0.76 – 1.60)
(0.60 – 1.61)
(0.67 – 1.18)
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O2 toxic yet essential
What oxygenation levels to aim for?
Usher 1973, reported much slower resolution
of acute lung disease in preterm infants when
PaO2 goal was 80-120 mmHg compared to
goal of > 40
STOP-ROP showed that late O2 supplemental
therapy goal 96-99% sat worsened pulmonary
outcomes compared to 89-94% sat goal
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BOOST trial randomized infants with
established BPD to high or low saturation
groups
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High saturation no benefit, prolonged the need for
oxygen
Soft evidence of other adverse pulmonary outcomes
Reasonable goal: keep saturation around 90%
to limit pulmonary O2 exposure
Turn down O2 when sats are high!
Death or CLD (Best available definition)
iNO
Placebo
Kinsella 1999
40 / 48 (83%)
27 / 32 (84%)
0.99 (0.81, 1.21)
Srisuparp 2002
6 / 16 (38%)
4 / 18 (22%)
1.59 (0.55, 4.62)
Schreiber 2003
43 / 105 (41%)
56 / 102 (55%)
0.77 (0.57, 1.04)
Hascoet 2005
42 / 61 (69%)
51 / 84 (61%)
1.11 (0.85, 1.43)
INNOVO 2005
54 / 64 (84%)
56 / 62 (90%)
0.93 (0.82, 1.07)
Van Meurs 2005
170 / 224 (76%)
174 / 225 (77%)
0.98 (0.88, 1.09)
Kinsella 2006
292 / 398 (73%)
294 / 395 (74%)
0.99 (0.91, 1.08)
4 / 20 (20%)
8 / 20 (40%)
0.53 (0.19, 1.46)
Ballard 2006
165 / 294 (56%)
184 / 288 (64%)
0.85 (0.74, 0.98)
EUNO 2008
134 / 399 (34%)
137 / 401 (34%)
1.01 (0.83, 1.23)
OVERALL*
954 / 1629 (59%)
992 / 1627 (61%)
0.96 (0.91, 1.01) p=0.095
Trial
Dani 2006
RR (95% CI)
0.2
0.5
1
Favours iNO
2
5
Favours placebo
† Subhedar removed from the analysis as zero cell counts caused model instability.
* χ2 test for heterogeneity p > 0.05
Estimates derived from N=1000 iterations of log-binomial model using multiple outputation method.
Subgroup
Analyses
(death or CLD)
Nine small RCTs, methods quite variable, total
<600 infants
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Most harmful factor, probably end-inspiratory
lung stretch.
Therefore just limiting the Vt is not enough
Therefore « optimize » PEEP as well as
controlling tidal volume
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After surfactant PEEP of 3 adequate for infants who
remain in 21% O2
Vt of 4 mL/kg adequate
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Unable to find reliable information about
the effects of attempted aggressive weaning
and early extubation on incidence of BPD
Extubation does not increase metabolic rate,
or calorie consumption
Apnea usually increased
Less nosocomial sepsis
Less exposure to assisted ventilation by ETT,
presumably less severe lung injury: BPD
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Kavvadia et al performed an RCT of varying
fluid intakes in 168 VLBWs. 70,90,110, 120, 140,
150, 150 compared to restricted 40, 40-60, 70, 90,
110, 130, 1504. This study individualized Na
intake after day1 (0 was given day 1, and there
was no difference between the groups) and
found no difference in any clinical outcomes.
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RCT compared 3-4 mmol/kg/d Na over first 5 days of life to
ELBW infants, showed more hyperosmolarity and more BPD in
the group receiving sodium. (n=17)
RCT compared 4 mmol/kg/d of Na on day 2 and after to a group
who started Na only after losing at least 6% of their body weight
(25-30wk n=46). Intervention group: more rapid resolution of
lung disease2.
Tammela’s RCT compared two fluid regimes in 100 newborns
less than 1750g3, 50,60,70,80,90,120 ml/kg/d in restricted group,
then 150 until 4 wk, and 80,100, 120, 150 ml/kg/d in controls
followed by 200. In fact iv fluids contained a routine Na
concentration of 3 mmol/100ml, so was also an RCT of Na intake .
Infants who received more fluid (and more Na) had increased
BPD.
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Lorenz randomized 88 VLBWs (>750g) to liberal or
restricted fluid 70 to 80 mL/kg/d compared to 60
on day 1, increasing by a fairly complicated
schedule5.
Modest differences in Na intake after day 2, 1 vs
2.5 mM/kg/d. There were no clinically significant
differences found in outcomes, there was a minor
trend to more PDAs and more BPD with liberal
H2O and sodium intake.
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Data could be summarized as : sodium restriction
is associated with improved respiratory outcomes,
whereas fluid restriction has no particular benefit.
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Repair of lung injury requires both energy and
protein.
A retrospective case-control study of VLBW
infants showed an association of BPD with
poor energy and protein intake between weeks
2 and 4.
 deRegnier RA, Guilbert TW, Mills MM, Georgieff MK.
Growth failure and altered body composition are established
by one month of age in infants with bronchopulmonary
dysplasia. J Nutr 1996 Jan;126(1):168-75.
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Early intralipid may be associated with
increased BPD rates
Very early intralipid doubled mortality in
ELBW infants, 600-800g. Sosenko et al (1993)
Intralipid administration appears to increase
PVR (Prasertsom et al 1996 Arch Dis Child)
Also worsens pulmonary vascular responses to
hypoxia. (Piglet study. Barrington et al 1997)
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An RCT comparing a 5 to a 14 day delay in
introducing intralipid had no effect.
 Alwaidh MH, Bowden L, Shaw B, Ryan SW.
Randomised trial of effect of delayed intravenous
lipid administration on chronic lung disease in
preterm neonates. J Pediatr Gastroenterol Nutr. 1996
Apr;22(3):303-6.
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N=64, <1500 g
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Deficits in protein and energy appear on day
one in VLBW infants and progressively
worsen until day 14.
 Cooke RJ et al.
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The accumulated deficit is never recovered
Babies with the greatest deficit more likely to
have BPD.
 Ehrenkrantz R. et al Longitudinal growth of
hospitalized very low birth weight infants.
Pediatrics. 1999 Aug;104(2 Pt 1):280-9.
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This suggests that a more “aggressive”
approach to nutrition should decrease
pulmonary morbidity
Little good evidence from RCTs
 Randomised controlled trial of an aggressive nutritional
regimen in sick very low birthweight infants. Wilson DC,
Cairns P, Halliday HL, Reid M, McClure G, Dodge JA.
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Benitz W, J Perinatol 2011
Extensive systematic review
No evidence of benefit of any approach to the
PDA on BPD or survival.
Little evidence for or against screening echo
and treatment in asymptomatic phase
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Published systematic review: ineffective
 Specker B. L., deMarini S., Tsang R. C. Vitamin and
mineral supplementation. Sinclair J. C. Bracken M. B.
eds. Effective Care of the Newborn 1992:161-177 Oxford
University Press New York, NY
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Statistical association between presence of U.
urealyticum and chronic lung disease.
Very large numbers of observational studies,
inconsistent results
Biologically plausible
Randomized trials exist of erythromycin to
determine if erythromycin eradicates
Ureaplasma, and reduces BPD
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Schelonka 2005, systematic review
23 studies; total 2216 infants reported BPD28, and
8 studies with 751 infants reported BPD36.
Association between Ureaplasma colonization and
both BPD28 and BPD36, but substantial
heterogeneity (Q test statistic, P < 0.01).
The greatest contribution to effect was from the
studies enrolling fewer than 100 infants.,
Conclusion: Ureaplasma colonization associated
with higher rates of BPD, greatest effect in small
studies; reporting bias may be partially
responsible.
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Recent studies using PCR show strong
association between Ureaplasma in the lung
and BPD
Kotecha 2004, 17 patients 6 positive
Colaizy 2007, 139 patients 33 positive
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2 randomized trials
Lyon et al n = 75 (only 9 positive for U. u)
Jonsson et al n= 28
No effect seen on any clinically important
outcome. U. u colonization was reduced (but
not eliminated).
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Ballard HO, azithromycin
A total of 220 intubated infants <1250g (111 azithromycin, and 109
placebo).
Mortality was 18% with azithromycin group vs 22% for placebo
(P¼0.45).
BPD was 76% azithromycin vs 84% placebo (P¼0.2).
The multiple logistic regression analysis demonstrated an odds
ratio of 0.46 decrease in the chance of developing BPDor death for
the azithromycin group, but was not statistically significant.
BPD was 73% in the Ureaplasma subgroup with azithromycin vs
94% placebo (P¼0.03).
Analysis of patients in the Ureaplasma subgroup only, using the
exact logistic model demonstrated a decrease inBPDor death in
the azithromycin group with an estimated odds ratio of 0.026
(0.001–0.618, 95% confidence interval).
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224 infants between 750-1250g, cultures for Ureaplasma
74 (33%) infants had a positive culture for U urealyticum in
the first 3 day cultures.
BPD was significantly higher with U urealyticum (15.9% vs
36.4%; P < .01). However, multivariate logistic regression
analysis failed to reveal a significant association between the
presence of U urealyticum and BPD development (odds
ratio: 2.4 [95% confidence interval: 0.9-6.3]; P = .06).
Clarithromycin treatment resulted in eradication of U
urealyticum in 68.5% of the patients.
BPD was significantly lower in the clarithromycin group
than in the placebo group (2.9% vs 36.4%; P < .001).
Multivariate logistic regression analysis confirmed the
independent preventive effect of clarithromycin for the
development of BPD (odds ratio: 27.2 [95% confidence
interval: 2.5-296.1]; P = .007).
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Baier RJ, Loggins J, Kruger TE: Failure of
erythromycin to eliminate airway
colonization with ureaplasma urealyticum in
very low birth weight infants. BMC Pediatr
2003, 3(1):10.
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Unbiased studies evaluating PCR detection of
Ureaplasma in high risk infants, and RCTs of
an effective anti-Ureaplasma agent
(azithromycin or clarithromycin)
Meta-analysis of the effects of postnatal steroids on neurodevelopmental impairment among
surviving, followed up, infants.
Studies are displayed in order of the degree of known contamination of the randomization,
Fitzhardinge and O'Shea known to have no contamination, Yeh, Shinwell, and Jones with
progressively increasing degrees of contamination, and Cummings, Subhedar and Vincer unknown.
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CAP trial
Death or BPD 39% with caffeine, 49% in
controls
Mortality not affected
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Antenatal steroids; possibly effective for
BPD prevention, improve survival.
Prophylactic natural surfactant compared to
no treatment
Prophylactic natural surfactant compared to
rescue treatment
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Prophylactic natural surfactant compared to
CPAP with early rescue; next slide.
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Vitamin A; IM level 1, other routes?
Fluid restriction
Antibiotic treatment of PPROM
High frequency oscillation with early volume
recruitment compared to standard approach
IMV
Moderately early postnatal steroids; but
adverse long term neurodevelopmental effects.
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Permissive hypercapnia
Delaying intralipid
Limit oxygen therapy
Inositol; probably effective if no surfactant
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Antenatal TRH
Vitamin E
Erythromycin
SOD
Sodium cromoglycate
Prophylactic bronchodilators?
Diuretics during acute RDS
Inhaled steroids
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Inhaled nitric oxide, ? Now proven? Other
studies in progress.
Early ibuprofen for asymptomatic PDA.
Azithromycin treatment of Ureaplasma
colonized infants
New ventilation techniques
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Volume guarantee, pressure support, improved
synchronization
Optimal fluid management
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Infants due to deliver before 34 weeks: antenatal
steroids, single course. Antibiotics (including
erythromycin) for at least 5 days if PPROM. (azith or
clarith probably better)
Infants delivering before 28 weeks: CPAP in the
delivery room, using a stable method that can be
continued to the NICU.
Gentle ventilation in the delivery room, (using tidal
volume limitation?)
Intubation for CO2 only if over 65mmHg
Intubation for FiO2 if over 40% (or perhaps earlier if
progressive)
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If require intubation, and O2: surfactant as soon as
possible, (then rapidly extubate to nIMV)
Low tidal volume ventilation (4 to 5 mL/kg) with
permissive hypercapnia, allow PaCO2 up to 65. Or
Elective high frequency oscillation with volume
recruitment
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Restrict sodium intake until day 3 or until 5% weight
loss
Administer vitamin A, (not in TPN bag, unless whole
system including tubing is protected from light!)
Early nutrition to achieve >80 calories as fast as possible
Insulin to allow adequate calories if required
Early feeds and early feed advancement at least 20
mL/kg/d.
? Delay introduction of intralipid (for ? 2 days)
Inhaled Nitric Oxide for infants still intubated at 7 to 21
days of age, continue for 24 days.
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Aim for O2 saturation 88- 92%
?Treat PDA as soon as diagnosed, before
symptoms, routine echocardiography to detect
asymptomatic PDA
Extubate early using caffeine/nIMV
Avoid postnatal steroids if possible